A transdermal delivery system is a pharmaceutical composition of matter which is applied to the skin in order to deliver a drug through the skin so as to achieve a systemic therapeutic effect as distinguished from a local therapeutic effect.
If a drug exhibits transdermal fluxes that are too low to provide the desired effect, a flux enhancer may be utilized to increase the transdermal flux. A flux enhancer is a substance, usually a solvent or vehicle, that is applied to the skin in combination with a drug to increase the transdermal flux of the drug. Enhancers are believed to function by disrupting the skin barrier or by changing the partitioning behavior of the drug to the skin.
With or without an enhancer, the transdermal flux determines whether percutaneous administration will provide sufficient drug absorption to achieve therapeutic systemic concentrations. Transdermal flux is a function of the drug's molecular diffusivity, partition coefficient and solubility in the skin.
The applicants have discovered that certain pharmacologically active chiral compounds may be administered transdermally as the resolved pure enantiomer or as a enantiomeric mixture containing a disproportionate amount of one enantiomer and substantially higher fluxes will be achieved than with the transdermal administration of a racemic modification of the same compound using the same vehicle system. It will be understood when reference is made to the enantiomer it is meant also include the substantially pure enantiomer which may contain very small amounts of the other enantiomer.
Accordingly, it is a primary object of this invention to provide compositions of an enantiomer of a pharmacologically active chiral compound or an enantiomeric mixture containing a disproportionate mixture of one enantiomer of a pharmacologically active chiral compound with or without a flux enhancer that will provide high transdermal flux when applied to the skin.
It is also an object of the invention to provide a novel method of transdermally administering pharmacologically active compositions which contain an enantiomer or an enantiomeric mixture containing a disproportionate amount of a pharmacologically active chiral compound.
As used herein and in the appended claims, the term enantiomeric mixture is used to define a mixture containing two enantiomers in any proportion. The term racemic modification is used to define an assembly of chiral molecules one-half of which are mirror images of the other. In the solid state, enantiomeric mixtures may be classified as (1) racemic conglomerates, (2) racemic compounds or (3) solid solutions. This classification appears in H.W.B. Roozeboom, Z. Physik. Chem. 28, 494 (1899); H. Mariser, Chem. Ber. 90,307 (1957) and Eliel, E.L., Stereochemistry of Carbon Compounds, McGraw Hill Book Co., Inc. NY 1962, Chapter 4, pp. 31-86 which are incorporated by reference. The term disproportionate mixture of enantiomers is used to include enantiomeric mixtures having other than 50:50 ratio of enantiomers.